Human adrenergic receptors are integral membrane proteins which have been classified into two broad classes, alpha and the beta adrenergic receptors. Both types of receptors mediate the action of the peripheral sympathetic nervous system upon binding of catecholamines, norepinephrine and epinephrine.
Norepinephrine is produced by adrenergic nerve endings, while epinephrine is produced by the adrenal medulla. The binding affinity of adrenergic receptors for these compounds, forms one basis of classification: alpha receptors tend to bind norepinephrine more strongly than epinephrine. The preferred binding affinity of these hormones is reversed for the beta receptors. In many tissues, the functional responses, such as smooth muscle contraction, induced by alpha receptor activation are opposed to responses induced by beta receptor binding.
Subsequently, the functional distinction between alpha and beta receptors was further highlighted and refined by the pharmacological characterization of these receptors from various animal and tissue sources. As a result, alpha and beta adrenergic receptors were further subdivided into alpha-1 (α1), alpha-2 (α2), beta-1 (β1), and beta-2 (β2) subtypes.
Alpha adrenergic agents are known in the art. Whereas alpha-1 agonists are known to include compounds which have vasoconstrictor activity and are thus useful for controlling intraocular bleeding, alpha-2 agonist are known to include compounds useful for reducing intraocular pressure (anti-glaucoma effect), for increasing renal flow (diuretics) and for altering the rate of fluid transport in the gastrointestinal tract (anti-diarrheals).
In “Heteroaromatic Analogues of the alpha.sub.2-Adrenoreceptor Partial Agonist Clonidine” J. Med. Chem. 1989, 32, 1627-1630, Chapleo et al. describe 6-(2-iminoimidazolidine)-3-oxo-3,4-dihydro-(2H)-1,4-benzoxazine and 7-(2-iminoimidazolidine)-3-oxo-3,4-dihydro-(2H)-1,4-benzoxazi compounds as partial alpha-2 agonists.
“Analogs of UK 14,304: Structural Features Responsible for α2 Andrenoceptor Activity”, Bioorg. & Med. Chem. Letters, Vol 5, No. 15, pp 1745-1750 describes aminoimidazoline derivatives with α2 activity.
U.S. Pat. No. 3,890,319 discloses 2-imidazolin-2-yl-amino-substituted quinoxalines as regulators of the cardiovascular system.
U.S. Pat. No. 4,515,800, describes 2-(trisubstituted phenylimino)imidazoline compounds [also known as 2-(trisubstituted-anilino)-1,3-diazacyclopentene-(2) compounds] in pharmaceutical compositions, preferably in eye drops, for the treatment of glaucoma.
U.S. Pat. No. 4,587,257 discloses 2-(trisubstituted phenylimino)imidazoline compounds capable of controlling ocular bleeding.
U.S. Pat. No. 3,636,219 discloses 2-(substituted-phenylamino)-thiazolines and imidazolines having anticholinergic activity.
U.S. Pat. No. 5,091,528 discloses 6- or 7-(2-imino-2-imidazolidine)-1,4-benzoxazines as alpha adrenergic agents having alpha adrenergic activity and useful for the treatment of glaucoma, renal and gastrointestinal disorders and vasoconstrictors.
Compound (+/−) 3,4-dihydro-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-2H-pyrrol-5-amine CAS 753464-99-2 is available from Aurora Screening Library.
Functional differences between alpha-1 and alpha-2 receptors have been recognized, and compounds which exhibit selective binding between these two subtypes have been developed. Thus, in WO 9200073 for example, the selective ability of the R(+) enantiomer of terazosin to selectively bind to adrenergic receptors of the alpha-1 subtype was reported. The alpha-1/alpha-2 selectivity of this compound was disclosed as being significant because agonist stimulation of the alpha-2 receptors was said to inhibit secretion of epinephrine and norepinephrine, while antagonism of the alpha-2 receptor was said to increase secretion of these hormones. Thus, the use of non-selective alpha-adrenergic blockers, such as phenoxybenzamine and phentolamine, was said to be limited by their alpha-2 adrenergic receptor mediated induction of increased plasma catecholamine concentration and the attendant physiological sequalae (increased heart rate and smooth muscle contraction).
The cloning, sequencing and expression of alpha receptor subtypes from animal tissues has led to the subclassification of the alpha-1 adrenoreceptors into alpha-1A, alpha-1B, and alpha-1D. Similarly, the alpha-2 adrenoreceptors have also been classified alpha-2A, alpha-2B, and alpha-2C receptors. Each alpha-2 receptor subtype appears to exhibit its own pharmacological and tissue specificities. Compounds having a degree of specificity for one or more of these subtypes may be more specific therapeutic agents for a given indication than an alpha-2 receptor pan-agonist (such as the drug clonidine) or a pan-antagonist.
Among other indications, such as the treatment of glaucoma, hypertension, sexual dysfunction, and depression, certain compounds having alpha adrenergic receptor agonist activity are known analgesics. However, many compounds having such activity do not provide the activity and specificity desirable when treating disorders modulated by alpha adrenoreceptors. For example, many compounds found to be effective agents in the treatment of pain are frequently found to have undesirable side effects, such as causing hypotension and sedation at systemically effective doses.